Brexanolone inhibits key systemic inflammatory pathways associated with post-partum depression

Post-partum depression (PPD) develops after childbirth and affects both the mother's and the infant's health by preventing healthy bonding. Women with PPD experience intense anxiety, feelings of depression, sleeplessness, inability to care for their child, and risk for suicide.

Brexanolone, an IV infusion comprised of a derivative of progesterone, was approved by the U.S. Food and Drug Administration for the treatment of PPD in 2019. The fast-acting medication significantly reduces depression symptoms and provides effects for up to 90 days. However, exactly how the drug provides these therapeutic effects has remained a mystery – until now.

A research team led by A. Leslie Morrow, PhD, the John Andrews Distinguished Professor of Psychiatry and Pharmacology in the UNC School of Medicine, has found that brexanolone works within the body by inhibiting the key systemic inflammatory pathways that are associated with depression. The new finding is monumental in that it suggests that PPD is likely caused, at least in part, by inflammation.

We found that brexanolone inhibited the toll-like receptors responsible for the production of cytokines and chemokines – the markers of inflammation."

A. Leslie Morrow, PhD, the John Andrews Distinguished Professor of Psychiatry and Pharmacology, UNC School of Medicine

Toll-like receptors are like gatekeepers on the surface of cells, recognizing molecules and then initiating a cell's inflammatory response. "Our results provide the first human data showing that blockade of specific inflammatory pathways is likely involved, at least in women who were unresponsive to other medications."

Their results were published in eBioMedicine.

According to recent studies, one in eight women experience post-partum depression symptoms, and the prevalence of depression diagnoses at delivery is rising. The CDC reports that rates in 2015 were seven times higher than they were in 2000. However, scientists are still unsure of what causes PPD to develop in the brain.

One potential cause of PPD could be deficiency in GABAergic transmission, which calms the brain via a neurotransmitter known as GABA. GABA, or y-Aminobutyric acid, is found in our central nervous systems and instructs our bodies to stop, or inhibit, the activity of neurons. Additionally, PPD could also be caused by deficits in our normal responses to stress.

But recent data and this new study suggest that inflammation may be contributing to the syndrome.

PPD is typically treated with SSRIs, much like other types of depression, but sometimes patients don't respond to conventional therapy. In such cases, physicians can now prescribe brexanolone. However, the mechanism underlying brexanolone's antidepressant effect was unclear when it was first approved.

The study indicates that the therapeutic effects of brexanolone are likely caused by its ability to inhibit toll-like receptor pathways and reduce inflammatory markers, since the inhibition of these pathways predicted therapeutic efficacy in the study. Since the same inflammatory markers have been shown to be up-regulated in PPD, it is likely that the condition is caused, at least in part, by inflammation.

By the same reasoning, other forms of depression that exhibit the elevation of inflammatory markers may also respond to brexanolone or other anti-inflammatory compounds. The team hopes that their new findings may lead to more cost-effective treatments that can block the same inflammatory pathways that were identified in the study.

The UNC School of Medicine leads the country in the clinical aspects of brexanolone treatment, thanks to collaborations across various departments.

"It was our collaboration with clinicians here that allowed us to test novel laboratory findings in PPD patients and determine if the effects of brexanolone in the blood were related to its therapeutic efficacy," said Morrow.

Riah Patterson, MD, assistant professor in the Departments of Psychiatry and Emergency Medicine and medical director of the Clinical Brexanolone Treatment Program and the Perinatal Psychiatry Inpatient Unit, directs the Women's Mood Disorder service that provides this treatment at UNC Hospitals. She co-authored the eBioMedicine paper, managed the patients' care, and collected the clinical data throughout the study.

Holly Krohn contributed to clinical data collection, while Samantha Meltzer-Brody, MD, MPH, the Assad Meymandi Distinguished Professor and Chair of Psychiatry, provided the leadership that established this service. She was also the lead investigator on the original clinical trials for Brexanolone.

Irina Balan, PhD, who was co-first author of the paper, conducted the blood measurements of inflammation and data analysis with the help of Giorgia Boero, PhD and Todd O'Buckley, BS, who also measured neurosteroids in patient blood by gas chromatography and mass spectrometry.